Four years ago, I proposed a new model of the immune system (the Danger model) based on the assumption that the immune system?s function is to discriminate between dangerous and harmless things rather than self and non-self. Because this model has tremendous implications for such subjects as cancer, transplantation, neonatal vacccines, parasitology, and autoimmunity, we have begun to test its basic premises and its applicability in several areas.1) TESTING THE BASIC PREMISES:a) Danger signals from injured tissues initiate immune responses. We found that1) necrotic but not apoptotic cells can induce activation of dendritic cells in vitro and in vivo2) molecules secreted by virus infected cells can also induce dendritic cell activation3) these Danger signals can be used as adjuvants to elicit an immune response in vivo against the protein antigen, OVA2) TRANSPLANTATION:A) orthotopic liver transplants:1)Livers transplanted across major histocompatibility barriers are accepted. With time, some of the recipients become tolerant of donor MHC class I molecules, as assayed by CTL activity, but not of donor MHC class II, measured in a proliferation assay.B) Skin grafts to immuno-incompetent mice.1) donor T cells from a transplantated skin can remain viable and active for months after the transplant. If the graft is removed, the T cells nevertheless remain in the recipeint nodes for weeks. These donor T cells can seve as a source of antigen to prime newly entering mature T Cells to induce rejection of the the graft. They can also traffic to the thymus of the recipient and induce tolerance of newly developing T cells2) T cells maturing in an animal carrying a long-healed skin graft nevertheless reject that graft, showing that the T cells do not exit the thymus in a tolerizable only state. These data contradict all known models of central and peripheral tolerance. - Immunology, danger, tolerance and transplantation.